Actinin-4 splice variant - a complementary diagnostic and prognostic marker of pancreatic neuroendocrine neoplasms

Xu, Xin; Honda, Kazufumi; Miura, Naruhisa; Hori, Shutaro; Blanc, Solange Le; Bergmann, Frank; Gaida, Matthias M.; Volkmar, Michael; Schimmack, Simon; Hackert, Thilo; Strobel, Oliver; Felix, Klaus

doi:10.7150/jca.37503

Cited by 4 publications

(3 citation statements)

References 32 publications

(46 reference statements)

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“…Actinin-4 splice variant ( Actn-4sv ) is also expressed in PanNENs, but not in normal islets cells. This splice variant is more expressed in low-grade tumors and positively correlated with survival of patients [ 55 ]. Splicing variant of the Receptor for Hyaluronic Acid-Mediated Motility (RHAMM B ), which is highly expressed in PanNENs, has been used to specifically deliver a small interfering RNA against another splicing variant related with apoptosis inhibition: Bcl-xL, which may be used as a novel therapy in PanNENs [ 56 ].…”

Section: Rna Biology and Surveillancementioning

confidence: 99%

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

Blázquez‐Encinas

Moreno-Montilla

García-Vioque

et al. 2022

Rev Endocr Metab Disord

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Neuroendocrine neoplasms (NENs) comprise a highly heterogeneous group of tumors arising from the diffuse neuroendocrine system. NENs mainly originate in gastrointestinal, pancreatic, and pulmonary tissues, and despite being rare, show rising incidence. The molecular mechanisms underlying NEN development are still poorly understood, although recent studies are unveiling their genomic, epigenomic and transcriptomic landscapes. RNA was originally considered as an intermediary between DNA and protein. Today, compelling evidence underscores the regulatory relevance of RNA processing, while new RNA molecules emerge with key functional roles in core cell processes. Indeed, correct functioning of the interrelated complementary processes comprising RNA biology, its processing, transport, and surveillance, is essential to ensure adequate cell homeostasis, and its misfunction is related to cancer at multiple levels. This review is focused on the dysregulation of RNA biology in NENs. In particular, we survey alterations in the splicing process and available information implicating the main RNA species and processes in NENs pathology, including their role as biomarkers, and their functionality and targetability. Understanding how NENs precisely (mis)behave requires a profound knowledge at every layer of their heterogeneity, to help improve NEN management. RNA biology provides a wide spectrum of previously unexplored processes and molecules that open new avenues for NEN detection, classification and treatment. The current molecular biology era is rapidly evolving to facilitate a detailed comprehension of cancer biology and is enabling the arrival of personalized, predictive and precision medicine to rare tumors like NENs. Supplementary Information The online version contains supplementary material available at 10.1007/s11154-022-09771-4.

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Section: Rna Biology and Surveillancementioning

confidence: 99%

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

Blázquez‐Encinas

Moreno-Montilla

García-Vioque

et al. 2022

Rev Endocr Metab Disord

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“…CgA is a protein that is secreted by the neuroendocrine cells of the pancreas and is often elevated in patients with PanNETs, being considered a good diagnostic and prognostic biomarker. [48][49][50] Additionally, synaptophysin is a protein that is expressed in the neuroendocrine cells of the pancreas and is often used as an immunohistochemical marker for PanNETs, as well as a useful prognostic marker, [51][52][53] as it is associated with worse patient outcomes. [53] Insulinomas pose significant diagnostic challenges due to their small size and diverse clinical presentations.…”

Section: Histopathology Immunohistochemistry and Biomarkersmentioning

confidence: 99%

A review of functional pancreatic neuroendocrine tumors: Exploring the molecular pathogenesis, diagnosis and treatment

Alshareefy,

Cummins,

Mazzoleni

et al. 2023

Medicine

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Pancreatic neuroendocrine tumors (PanNETs) are a rare subtype of pancreatic cancer and can be divided into functional (30–40%) and nonfunctional subtypes. The different subtypes of functional PanNETs (F-PanNETs) have a variety of classical presentations that raise suspicion for an underlying PanNET. It is estimated that 90% of PanNETs are sporadic, and the PI3K-Akt-mTOR and ATRX/DAXX signaling pathways have been recognized as key genetic pathways implicated in the pathogenesis. The other 10% of PanNETs may occur in the context of familial cancer syndromes such as MEN1. Chromogranin A is the most useful biomarker currently; however, several studies have shown limitations with its use, especially its prognostic value. Synaptophysin is a novel biomarker which has shown promising preliminary results however its use clinically has yet to be established. Blood tests assessing hormone levels, cross-sectional imaging, and endoscopic ultrasound remain at the core of establishing a diagnosis of F-PanNET. The treatment options for F-PanNETs include surgical methods such as enucleation, systemic therapies like chemotherapy and novel targeted therapies such as everolimus. The prognosis for F-PanNETs is more favorable than for nonfunctional PanNETs, however metastatic disease is associated with poor survival outcomes. Researchers should also focus their efforts on identifying novel pathways implicated in the pathogenesis of F-PanNETs in order to develop new targeted therapies that may reduce the need for surgical intervention and on the establishment of novel biomarkers that may reduce the need for invasive testing and allow for earlier detection of F-PanNETs.

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“…Specifically, 98% of introns are processed by the major spliceosome, while the remaining are spliced by the minor spliceosome, which share most of their components but differ in a limited set of U RNAs and accompanying splicing factors [ 15 ]. Interestingly, there is now ample evidence that alternative splicing is commonly dysregulated in all tumors and cancers examined [ 16 , 17 ], including pancreatic NENs and SCLC [ 18 – 21 ]. This dysregulation may lead to the appearance of aberrant splicing variants imparting malignant properties to cancer cells, and has emerged as a transversal hallmark pervading all the other cancer hallmarks [ 20 , 22 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery

Blázquez-Encinas,

García-Vioque,

Caro-Cuenca

et al. 2023

J Transl Med

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Background Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. Methods We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. Results The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. Conclusions These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

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Actinin-4 splice variant - a complementary diagnostic and prognostic marker of pancreatic neuroendocrine neoplasms

Cited by 4 publications

References 32 publications

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

The uprise of RNA biology in neuroendocrine neoplasms: altered splicing and RNA species unveil translational opportunities

A review of functional pancreatic neuroendocrine tumors: Exploring the molecular pathogenesis, diagnosis and treatment

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery

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